The topic of testosterone and cardiovascular disease has been receiving a lot of attention over the past years. Despite the common belief that testosterone may increase the incidence of coronary artery disease, the scientific evidence shows the opposite; testosterone deficiency is associated with increased prevalence and severity of coronary atherosclerosis and testosterone therapy is associated with beneficial cardiovascular outcomes.1

To date, no long-term studies have assessed the effects of testosterone therapy in men with a history of cardiovascular disease. Here we summarise the results of an observational study that investigated the effects of long-term testosterone therapy - up to 8 years - in hypogonadal men with a history of
cardiovascular disease.2

Key Points

In men with testosterone deficiency and a history of cardiovascular disease, who received testosterone therapy for up to 8 years, a significant weight loss (from 114 kg to 91 kg) and a decrease in waist circumference (112 cm to 99 cm) was observed. BMI decreased from 37 to 29.

No patient suffered a major adverse cardiovascular event during the full observation time.

In men with testosterone deficiency, testosterone therapy appears to be effective in achieving sustained improvements in all cardiometabolic risk factors, and may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.

What is known

A rapidly growing body of evidence has documented that testosterone deficiency negatively impacts men's overall health and quality of life3, as well as increases cardiometabolic risk and all-cause and cardiovascular mortality.1,4-7 In line with this, higher testosterone levels are associated with lower incidence of sudden cardiac arrest.8

Decades of research and clinical practice has proven testosterone therapy to be an effective and safe treatment of testosterone deficiency, including patients with peripheral vascular disease and angina pectoris.1 Despite this, a few flawed studies reported controversial outcomes9-12, followed by additional warnings required by the FDA in the labels of testosterone products. However, more recent medium-term studies have refuted all negative claims.13-18

What this study adds

In two urological clinic observational registries, 77 men with testosterone deficiency (aged 43 to 68 years, mean 62 years old) who had a history of cardiovascular disease, were identified. The effects of testosterone therapy – using long-acting injections of testosterone undecanoate at 3-monthly intervals - on anthropometric and metabolic parameters were investigated for up to 8 years. Any occurrence of major adverse cardiovascular events was reported.

52% of the subjects had a previous MI, and 9% had a previous stroke. A previous diagnosis of CAD had been made in 62% of the subjects. In all, 53% had type 2 diabetes. Furthermore, 94% of the subjects were on antihypertensives, 75% on statins, and 48% on antidiabetic medications.

In men with testosterone deficiency and a history of cardiovascular disease, who received testosterone therapy for up to 8 years, a significant weight loss (from 114 kg to 91 kg) and a decrease in waist circumference (112 cm to 99 cm) was observed. BMI decreased from 37 to 29.

Cardio-metabolic parameters such as lipid profile, glycemic control, blood pressure and heart rate improved significantly and sustainably throughout the observation period. Also, there was a marked and significant reduction in pulse pressure from 65 to 57. The reduction in pulse pressure was gradual and significant over the course of treatment versus baseline. At the end of the 8-year follow-up, the mean reduction in pulse pressure was 9 (figure 1). In addition, there was a marked reduction in non-HDL, from 241 mg/dL to 108 mg/dL (figure 2).

Figure 1: Pulse pressure in hypogonadal men with a history of cardiovascular disease receiving long-term treatment with testosterone undecanoate.

Haider A et al. Vasc Health Risk Manag 12: 251-261 (2016)

Figure 2: non-HDL cholesterol levels in hypogonadal men with a history of cardiovascular disease receiving long-term treatment with testosterone undecanoate.

Haider A et al. Vasc Health Risk Manag 12: 251-261 (2016)

No patient had a major adverse cardiovascular event during the full observation time, and no urological events (prostate cancer or voiding dysfunction) were incurred. None of the patients dropped out, and none missed a single injection.

Comments

This study is notable in that it shows that long-term testosterone therapy is safe in clinical practice, even in men with a history of cardiovascular disease. This study also confirms previous reports of marked reductions in body weight and waist circumference and improved lipid profile, glycemic control, and blood pressure with long-term testosterone therapy.19-21

Importantly - considering the alleged cardiovascular risk of testosterone therapy - this study shows that during 8 years of continuous testosterone therapy with 100% adherence, there were no major adverse cardiovascular events. Supporting the cardiovascular safety of testosterone therapy are the beneficial effects on lipid profile, glycemic control, blood pressure, heart rate, and pulse pressure. It is notable that these improvements occurred even though patients were treated with statins. This suggests that statin treatment alone is inadequate, and that co-treatment with testosterone therapy provides greater efficacy in secondary prevention patients.

Pulse pressure (the difference between systolic and diastolic pressure) is an independent marker of cardiovascular risk22, and any reduction in this parameter is considered favorable for reducing CVD risk.23 The mean reduction in pulse pressure by 9 is clinically significant. A meta-analysis shows that when comparing the highest pulse pressure category with the lowest category, individuals with the highest pulse pressure have an 80% and 32% increased risk of CV and all-cause mortality, respectively.24 The robustness of pulse pressure as a risk factor was reinforced by the clear relationship of pulse pressure as a continuous risk estimate (per 10 mmHg increment) with CV and all-cause mortality, independent of all other confounding. For each 10 mmHg increment in pulse pressure, the risk of cardiovascular mortality and all-cause mortality was 1.13 and 1.09, respectively.23

It is also notable that long-term testosterone therapy markedly reduces non-HDL cholesterol levels even in men who are on statins. In this study, non-HDL dropped from 241 to 108 mg/dL. This is similar to what was found in a previous long-term registry study in men without a history of cardiovascular disease, which we reported in a previous editorial "Effects of Testosterone Therapy for up to 10 years on Obesity and Metabolic Parameters".

The fact that the majority of patients were on concomitant medications (antihypertensives, lipid-lowering drugs, and antidiabetic medications) with limited success raises the question of medication adherence, which is known to be low in chronic diseases. It is therefore notable that the adherence in this study was 100%. One explanation for this may be that testosterone undecanoate only needs to be administered once every 12 weeks, and always needs to be administered in the doctor's office.

While randomized controlled trials (RCT) are considered the gold standard in medical research, observational and registry studies provide valuable real-life data and relevant information on the benefits and risks to patients in routine daily clinical practice.25 Specifically, observational / registry studies provide critical information on the long-term safety and effectiveness of testosterone therapy in clinical practice, as well as real-life adherence – which ultimately impacts the therapeutic efficacy of any treatment - in the general population.25 Long-term safety and effectiveness cannot be studied in RCTs because of astronomical costs, and real-life adherence can only be studied in observational real-life settings.